We need more studies to find out how common this is for children with autism and gender dysphoria.

In addition, we need studies to look at how persistence and desistence from gender dysphoria work for children with autism. Is the developmental process different from neurotypical children? How should parents, educators, and therapists work with children who have both autism and gender dsyphoria?

As the authors say, “Careful long-term clinical observation and further studies are needed.”

More details on the boy’s gender dysphoria:

[The boy came to the clinic at age 5 for behaviors related to autism] At the age of 7, he verbalized a strong aversion to being a boy and desired to be a girl. The boy behaved as if he were a girl and preferred to play with girls. Based on his clinical symptoms that lasted more than 6 months, the comorbid diagnosis of GID was made according to ICD-10 criteria.

After entering school, he exhibited behaviors such as using stationery with Disney princesses and dressing himself in clothes with flowers. He rarely went to the bathroom because he did not want to be seen urinating in a standing position. He skipped swimming classes at school to avoid exposing his chest. Only at his home, the boy wore skirts and makeup. At school, he was bullied by classmates because of his feminine behaviors. However, as school teachers were supportive and intervened appropriately, he never refused to attend school.*”

“At the age of 11, when puberty started, he became confused and repeatedly shaved his body hair. He tried to keep his voice tone high. However, as puberty progressed his gender dysphoria gradually alleviated.

In Japan, in general, junior high school students are required to wear school uniforms based on their biological sex, typically a skirt for girls and trousers for boys. They are also requested to obey school regulations related to length of hair, though the strictness is highly school-dependent. Our patient entered a public school in his residential district and had to behave as a typical male student. As a consequence, his gender-related manifestations fell below the threshold for the diagnosis of GID as of age 16 (the time of this writing).”

Note: This is not just a question of changes in behavior – the authors also say that his gender dysphoria gradually alleviated as he went through puberty. In addition, the authors got informed written consent before publishing this study.

*School refusal is a significant problem for students with gender dysphoria in Japan. (Bullying seems to be a problem everywhere.)

Twin and family studies suggest that there may be a genetic component to gender dysphoria. Researchers have naturally been trying to find genes linked to gender dysphoria.

Most of the research has focused on genes that are known to be related to sex hormones in some way.

I. Researchers may have found genes related to gender dysphoria in trans men (born female).

A large Spanish study found an association between the gene for Estrogen Receptor β and gender dysphoria, but a medium-sized Japanese study did not.

A small Austrian study found an association between gender dysphoria and a different gene related to converting progesterone into androgens. Nobody else has looked at this gene.

A possible flaw with the Austrian study is that the control females were seeking help with perimenopausal issues; it may be that their genes were different from the general public.

Both of these results need to be replicated.

It is also possible that the genes were related to sexual orientation.

In the Spanish study, all of the trans men were attracted to women; it is likely that 95% of the control women were attracted to men.

The Austrian study does not talk about sexual orientation, but typically most trans men are attracted to women and most women are not.

Many control women also had the genetic variations found in trans men. Some other genes or environmental factors must also be involved.

These results need to be replicated. The Austrian study was relatively small and possibly flawed while the Spanish and Japanese studies contradict each other.

II. Researchers thought they had found genes related to gender dysphoria in trans women (born male), but larger studies did not replicate the results. It is possible, however, that the genes related to gender dysphoria are different in different populations.

None of the studies found a relationship between gender dysphoria and the gene for CYP19A1.

Three studies found no difference in the gene for estrogen receptor β; the study that found a difference was much smaller than the others.

Three studies found no difference in the gene for androgen receptor, including one study of over 400 trans women.

III. An Italian study that looked at the Y chromosome found no differences between trans women and control males.

IV. An Austrian study that looked at sex chromosomes in trans women and trans men found no significant abnormalities.

V. A Japanese study that looked at genes related to estrogen receptor alpha and progesterone receptor found no differences between the genes of male to female transsexuals and male controls or the genes of female to male transsexuals and female controls. This study also looked at estrogen receptor β, androgen receptor, and CYP19A1 and found no differences for those genes either; this is one of the studies discussed above.

VI. An Austrian study of a gene related to steroid 5-alpha reductase (SRD5A2) found no differences between trans women, trans men, and male and female controls. SRD5A2 is involved in the conversion of testosterone to dihydrotestosterone.

It is important to remember that there may be some other genetic variations that are linked to gender dysphoria in trans women, something that we haven’t studied yet.

At this point, however, we do not seem to have found genes related to gender dysphoria in trans women.

Recommendations for future research:

Look at genes other than the ones related to sex hormones or sex chromosomes. Perhaps the cause of gender dysphoria is different from what we expect.

Control for sexual orientation by including some cis lesbians and gay men in the study.

Study trans people with African ancestry – and other groups that have not yet been studied. Studies so far have looked at people from Spain, Italy, Japan, Austria, America and Australia (Caucasian only), and Sweden.

They found no connection between the genes related to androgen receptors or aromatase, but they did find an association between the ERβ gene and gender dysphoria in trans men.

“The repeat numbers in ERβ were significantly higher in FtMs than in control group, and the likelihood of developing transsexualism was higher (odds ratio: 2.001 [1.15-3.46]) in the subjects with the genotype homozygous for long alleles.”

Three caveats:

All the trans men participating in the study had gender dysphoria that began before puberty and were attracted to women (i.e. members of their biological sex). The control females were probably 95% straight. It is possible that the genetic difference they found is related to sexual orientation, not gender identity.

This is not an absolute difference, it is a difference in frequency – 69% of the trans men had the long allele for ERβ, but so did 59% of the control women. Some other genes or environmental factors must also be involved in gender dysphoria (or sexual orientation).

The study below found different results; however, this study was larger.

They found no differences between the genes of male to female transsexuals and male controls or the genes of female to male transsexuals and female controls.

“The present findings do not provide any evidence that genetic variants of sex hormone-related genes confer individual susceptibility to MTF or FTM transsexualism.”

The abstract does not provide any information on the demographics of the trans women and trans men.

The results of this study for ERβ contradict the results of the Spanish study. The Spanish study looked at 273 trans men while this study only looked at 74, so it is unlikely that the Spanish study is simply wrong.

It may be, however, that this study is still right, at least in Japan. People in different countries have different genes; they may have different genes for gender dysphoria.

It is possible that cultural differences or medical policies may mean that clinics in different countries are looking at groups of people with different problems.

Finally, gender dysphoria might be caused by different factors or combinations of factors in different cultures. Japanese trans men may be different from Spanish trans men in some important way.

A possible flaw in this study is that the females controls were women seeking help with perimenopausal disorders; they may have had genes that were different from the general population. The male controls, on the other hand, were “participating in a health prevention program.”

Since the results found that the frequency of a particular mutation was different in female controls from all of the other groups, it matters a great deal if the control females are significantly different in some other way from the other participants.

This study looked at a different gene from the other studies, CYP17. CYP17 encodes cytochrome, an enzyme involved in converting progesterone and pregnenolone into androgens.

The authors found that a particular mutation of this gene, CYP17 −34 T>C, was associated with female to male transsexualism, but not male to female transsexualism.

They also found that, “the CYP17 −34 T>C allele distribution was gender-specific among controls. The MtF transsexuals had an allele distribution equivalent to male controls, whereas the FtM transsexuals did not follow the gender-specific allele distribution of female controls but rather had an allele distribution equivalent to MtF transsexuals and male controls.”

In other words, trans men and trans women were similar to male controls and not female controls.

They point out, however, that there were women without gender dysphoria who had the mutant allele as well as women with gender dysphoria who did not have it. “Thus, carriage of the mutant CYP17 T−34C SNP C allele is neither necessary nor sufficient for developing transsexualism.”

In other words, there must be other genetic or environmental factors involved.

They do not discuss the sexual orientation of the participants in the study. As discussed above, it is possible that most of the trans men were attracted to women and that this genetic mutation is related to sexual orientation, not gender identity.*

Finally, I keep coming back to the female control group. What if converting progesterone to androgens is related in some way to perimenopausal symptoms? What if the mutant gene protects against problems in menopause somehow and so the female control group includes fewer people with this gene?

2007:

A common polymorphism of the SRD5A2 gene and transsexualism. This Austrian study compared 100 trans women, 47 trans men, 755 control men, and 915 control women. They looked at a mutation of the steroid 5-alpha reductase gene (SRD5A2); this gene produces an enzyme that catalyzes the conversion of testosterone to dihydrotestosterone.

They found no differences between any of the groups. The mutant allele was not associated with transsexualism and its distribution was not gender specific among controls.

This study has the same flaw as the 2008 study listed above; the control females were all seeking help for problems with perimenopause.

2002:

Sex chromosome aberrations and transsexualism. This Austrian study looked at the chromosomes of 30 trans women and 31 trans men. They did not find significant abnormalities, although they suggested further investigation might be worthwhile.

“We could not detect any chromosomal aberrations with the exception of one balanced translocation 46,XY,t(6;17)(p21.3;q23). Importantly, no sex chromosomal aberrations, which would be detectable on the G-banded chromosome level, have been observed.”

They conclude:

“The data described here provide evidence that genetic aberrations detectable on the chromosome level are not significantly associated with transsexualism. In addition, molecular-cytogenetic FISH analyses did not reveal deletions of the androgen receptor gene locus on chromosome Xq12 or of the SRY locus on chromosome Yp11.3. Multiplex PCR analyses demonstrated one AZF deletion in a male-to-female transsexual.”

but:

“However, the detection of one carrier of a Y chromosome microdeletion out of 30 male-to-female transsexuals could argue for further investigations. This is of special interest in light of the recent discussion of gamete banking before hormonal and sex reassignment surgery of transsexuals.”

“This gender disorder does not seem to be associated with any molecular mutations of some of the main genes involved in sexual differentiation.”

The trans women were aged 24-39 and had already begun hormone therapy. A little over half of them had already had sex reassignment surgery and the rest were waiting for it.

2002:

Sex chromosome aberrations and transsexualism. This Austrian study looked at the chromosomes of 30 trans women and 31 trans men. They did not find significant abnormalities, although they suggested further investigation might be worthwhile.

Interestingly, 98% of the trans women had chromosomes that were 46,XY, i.e. normal, but 2% of the group showed aneuploidy, or abnormal chromosomal numbers. This is slightly higher than usual.

The abstract does not go into detail, but presumably the aneuploidies were cases of Klinefelter syndrome; a condition where a person typically has one Y chromosome and two X chromosomes. Most people with Klinefelter’s syndrome identify as male, but there may be a higher than usual occurrence of gender dysphoria among people with Klinefelter’s.

There are no details on the trans women in the abstract; however, the same researchers did a very similar study of trans men (see above). It may be that the participants in the two studies were screened in the same way.

This Australian and American study compared 112 male to female transsexuals to 258 control males. They looked at genes for androgen receptor, estrogen receptor beta, and aromatase. No differences were found for the estrogen receptor or aromatase, but transsexuals had longer repeat lengths for the androgen receptor allele.

This result was not found in the Spanish study or the Japanese study above. The Spanish study was larger than this one. Thus, this result has not been replicated.

However, it is possible that this genetic variation is connected to gender dysphoria for Caucasian trans women in America and Australia, but not in Spain or Sweden and not for Japanese trans women.

It is also possible that the genetic difference found here is related to sexual orientation, not gender identity. The researchers in this study only knew the sexual orientation for about 40% of the participants in the study, but people with gender dysphoria are much more likely to be attracted to people of the same biological sex than people without gender dysphoria.

As in the Spanish, study above, this is not an absolute difference, it is a relative one. There were also cis men who had long AR repeat lengths (Figure 1). Again, some other genes or environmental factors must also be involved in gender dysphoria (or sexual orientation).

The trans women in this study were all Caucasian; 76 of them were from an Australian clinic and 36 of them were from UCLA in America. Almost all of them were on hormones. Some of them had gender dysphoria in childhood. “The sexuality is only known for approximately 40% of patients, because some patients did not wish to discuss or disclose this information or the patient’s sexuality was flexible and not easily classified.”

This Swedish study compared the genes of 24 male to female transsexuals and 229 male controls. They looked at specific areas in the androgen receptor gene, the aromatase gene, and the estrogen receptor β gene.

They did not find a difference between male-to-female transsexuals and men for the first two genes, but they did find a difference related to the gene for estrogen receptor β. “Transsexuals differed from controls with respect to the mean length of the ERβ repeat polymorphism.”

In addition, “binary logistic regression analysis revealed significant partial effects for all three polymorphisms, as well as for the interaction between the AR and aromatase gene polymorphisms, on the risk of developing transsexualism.”

The study was very small, however, and as the authors said, “results should be interpreted with the utmost caution.”

The three more recent studies above did not replicate the findings of this study. The other studies were much larger than this one, so it is possible that these results were a fluke.

It is also possible, that the genes linked to gender dysphoria in Sweden are different from the genes linked to it in other countries.

The authors of the American-Australian study described above say, “Our sample size was approximately four times larger than that of the Swedish study, so it is possible that the former study was underpowered to detect a false positive. Alternatively, there might be differences between Swedish and non-Swedish populations in this polymorphism. In the Swedish study, the long repeat occurred in 51.8% of control subjects and 67.1% of transsexuals, whereas in the present study the long repeat occurred in 36.5% of control subjects and 44.1% of transsexuals. Thus, although there was a trend in the same direction in both studies, there are major differences in prevalence of these long repeats between the two populations.”

The only data we have on the participants in the study are that the trans women were Caucasian and the vast majority of the controls were also Caucasian. Again, it is likely that there was a higher percentage of people attracted to male in the group of trans women than the general population; this might have affected the results.

As the authors point out, “the gene variants investigated in this study are relatively common, none of the studied variants could hence be assumed to be the primary cause of this condition.” Rather, genes might increase or decrease the chance of developing gender dysphoria.

So, if the results of this study are not a fluke, we are still left with the questions of what other factors contribute to developing gender dysphoria and is this a gene related to gender dysphoria or sexual orientation in Sweden?

The end result of all this:

We have a couple of possible candidates for genetic variations related to gender dysphoria in trans men, but we need further studies. We need to replicate the results and to control for sexual orientation. In the case of the CYP 17 gene, we need to compare trans men to healthy control females instead of women with perimenopausal issues.

We don’t have any strong candidates for genetic variations related to gender dysphoria in trans women. Future studies might do well to look for genes that are not related to sex hormones. As always, they should control for sexual identity. (This should be done by adding lesbians and gay men without gender dysphoria, not by excluding trans women who are attracted to women from the studies. See my rants in articles on brain sex.)

*A group of trans women would include many more people attracted to men than a group of control males, but typically about half of trans women are attracted to women while most trans men are attracted to women. Thus this could be a comparison of two groups (control males and trans men) where a large majority of the people are sexually attracted to women, one group where half the people are attracted to women (trans women), and a group where about 5% of the people are attracted to women (control females).

This is a very short article, actually published as a letter to the editor.

The authors present a case of a boy who they diagnosed with both gender dysphoria and autism. (In a later follow-up study, they found that he no longer had gender dysphoria at age 16.)

They present this case study as a counter point to the “extreme male brain” theory of autism. As they say, with the extreme male brain theory, “gender dysphoria in female subjects with Asperger syndrome (AS) could be explained logically. But a literature search yielded no boys with AS and gender identity disorder (GID). Hereby we present such a case.”

The authors diagnosed the boy with gender dysphoria based on the following criteria: feminine behaviors and speech, preferring female playmates, preference for feminine activities, lack of interest in sterotypical boy toys, liking cute characters in cartoons, always painting cute girls surrounded with hearts and flowers, dressing in girls’ clothes at home, regretting being a boy, wishing he were a girl, and saying that he would grow up to be a woman.

The child was of average intelligence and had not had delays in developing motor skills or language. However, he had “limited interactions with others, difficulty in developing peer relationships and was underresponsive in social situations. He liked making his own rules and frequently lost his temper when there were broken.” He was also preoccupied with certain colors and figures.

The authors make a distinction between gender-related symptoms in autism and gender identity disorder:

“Most of the gender-related symptoms in autistic spectrum disorder (ASD) could be related to behavioral and psychological characteristics of autism. For example, a boy with ASD might have a sense of belonging to the female sex after being bullied by male peers. Tranvestism in ASD may arise from a preoccupation with specific clothes such as a flared skirt which satisfies their tactile sensation. In their youth, ASD subjects can sometimes develop a unique confusion of identity that occasionally expands to gender-related problems. But these views do not explain the present case. For the diagnosis of GID in ASD, sufficient language abilities and sufficient follow-up time are essential. The present case fulfills these requirements.”

The authors conclude by saying that if the GID persists, they would treat the patient following international standards – i.e. he would be allowed to transition following the same protocol as anyone else.

One thing I found interesting in this article was that one of the boy’s feminine behaviors was covering his mouth with his hand when he laughed. This is something women in Japan do, but not in the West. Clearly culture plays a role in how a child expresses their gender dysphoria.

This study looked at the patients at a Japanese clinic for gender identity disorder to see if they had any other mental health issues. They did not find a high rate of autism spectrum disorders (ASDs).

This is not a review of the full study, just the information related to ASD.

Out of 579 patients that they treated, only 4 were diagnosed with Asperger’s disorder and there were no other cases of autism spectrum disorders.

In other words, less than 1% of this group had an ASD.

All of the patients with Asperger’s were born male.

This data is worth noting because it is so different from results in other countries. Are patients with autism not referred to the GID clinic in Japan? Is autism being diagnosed the same way in the different studies? Are adult patients less likely to have ASD than children and teenagers with gender dysphoria?

This data also highlights the fact the gender dysphoria and autism spectrum disorders are connected in males, not just females – in fact, in this case, they were connected only in males.

There is a theory that having an “extreme male brain” makes some girls with autism develop gender dysphoria. While that could still be true, it does not explain why males with autism would feel that they are females.

Instead of an “extreme male brain,” there might be some other mechanism that connects autism and gender dysphoria in both trans women (born male) and trans men (born female).

Another interesting aspect of the data was that they diagnosed 96% of the patients they saw with GID. Of the 24 patients who were not diagnosed with GID, half had severe psychological disorders like schizophrenia. Eight were excluded for homosexuality and four were excluded for transvestic fetishism.

I am not sure why they diagnosed such a high percentage of their patients with GID. Perhaps by the time people are referred to their clinic, they have been diagnosed by other doctors. It might also be somehow related to the definition of GID or the process of diagnosis.

I am assuming they excluded the gay patients because the patients discovered that they did not have GID and that the clinic is not excluding all gay patients. Most people with GID are attracted to people of their birth sex.

Other important results from the abstact:

“Using DSM-IV criteria, 579 patients (96.0%) were diagnosed with GID. Among the GID patients, 349 (60.3%) were the female-to-male (FTM) type, and 230 (39.7%) were the male-to-female (MTF) type. Current psychiatric comorbidity was 19.1% (44/230) among MTF patients and 12.0% (42/349) among FTM patients. The lifetime positive history of suicidal ideation and self mutilation was 76.1% and 31.7% among MTF patients, and 71.9% and 32.7% among FTM patients. Among current psychiatric diagnoses, adjustment disorder (6.7%, 38/579) and anxiety disorder (3.6%, 21/579) were relatively frequent. Mood disorder was the third most frequent (1.4%, 8/579).”

The horrifying part has been bolded. I’m putting off talking about it until another day when I can deal with it.

I’ll just add that the authors suggested that “the harsh circumstances in which most GID patients have lived in Japan might influence the high rate of suicidal ideation or self mutilation in GID patients.”

In the abstract, the authors suggest that people with autism spectrum disorders (ASD) “often have identity crises which sometimes include gender dysphoria.” They speculate that when people with ASD become teenagers, they “realize their uniqueness and differences compared to others, and, as a result, they may develop confusion of identity which could be exhibited as gender identity disorder.”

They talk about a recent study that found that “amongst 204 children and adolescents who visited a GID clinic in the Netherlands, 7.8% were diagnosed with autism spectrum disorders after a careful diagnostic procedure by a multi-disciplinary team.”

The paper looks at four cases of young people with both ASD and either gender dysphoria or “related symptoms.” Their study included:

“1) a girl with PDD (pervasive developmental disorders=autism/ASD) who repeatedly asserted gender identity disorder (GID) symptoms in response to social isolation at school,

2) a junior high school boy with PDD and transvestism,

3) a boy diagnosed with Asperger’s disorder who developed a disturbance of sexual orientation, and

4) a boy with Asperger’s disorder and comorbid childhood GID.”

They believe that “Many of the clinical symptoms related to gender dysphoria might be explained by the cognitive characteristics and psychopathology of PDD.”

Without seeing more, it is hard to evaluate this study.

Nevertheless, they do not seem to have proven their case very well. Two of the four people they discuss do not sound like they have gender dysphoria.

For the other two children, it would help to know more details – did they outgrow the gender dysphoria? do they now believe that they were wrong about their gender? could they have gender dysphoria and ASD?

The authors conclude by saying that gender dysphoria has become more well-known in Japan and they are seeing more patients complaining of it.

They believe that it is important to consider an underlying diagnosis of ASD for patients with gender dysphoria; I can agree with that conclusion at least.